Interest in the transdermal delivery of high molecular weight beneficial agents such as peptides, proteins and oligonucleotides to the human body continues to grow with the increasing number of medically useful peptides, proteins and oligonucleotides becoming available in large quantities and pure form. The transdermal delivery of peptides, proteins and oligonucleotides still faces significant problems. In many instances, the rate of delivery or flux of such agents through the skin is insufficient to produce a desired therapeutic effect due to their large size/molecular weight and the resulting inability to pass through natural pathways (pores, hair follicles, etc.) through skin. In addition, polypeptides and proteins are easily degradable during penetration of the skin, prior to reaching target cells. Likewise, the passive flux of water soluble small (e.g., 200 to 500 dalton) agent molecules is often limited.
One method of increasing the transdermal delivery of agents relies on the application of an electric current across the body surface or on "electrotransport". "Electrotransport" refers generally to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body surface such as skin, mucous membranes, nails, and the like. The transport of the agent is induced or enhanced by the application of an electrical potential, which results in the application of electric current, which delivers or enhances delivery of the agent. The electrotransport of agents through a body surface may be attained in various manners. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process, involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, still another type of electrotransport, involves the passage of an agent through pores formed by applying a high voltage electrical pulse to a membrane. In many instances, more than one of these processes may be occurring simultaneously to different extents. Accordingly, the term "electrotransport" is given herein its broadest possible interpretation, to include the electrically induced or enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of the specific mechanism(s) by which the agent is actually being transported. Electrotransport delivery generally increases agent delivery, particularly large molecular weight species (e.g., polypeptides) delivery rates, relative to passive or non-electrically assisted transdermal delivery. However, further increases in transdermal delivery rates and reductions in polypeptide degradation during transdermal delivery are highly desirable.
One method of increasing the agent transdermal delivery rate involves pre-treating the skin with, or co-delivering with the beneficial agent, a skin permeation enhancer. The term "permeation enhancer" is broadly used herein to describe a substance which, when applied to a body surface through which the agent is delivered, enhances its flux therethrough. The mechanism may involve a reduction of the electrical resistance of the body surface to the passage of the agent therethrough, an increase in the permselectivity and/or permeability of the body surface, the creation of hydrophilic pathways through the body surface, and/or a reduction in the degradation of the agent (e.g., degradation by skin enzymes) during electrotransport.
There have also been many attempts to mechanically disrupt the skin in order to enhance transdermal flux, such as, U.S. Pat. Nos. 3,814,097 issued to Ganderton et al., 5,279,544 issued to Gross et al., 5,250,023 issued to Lee et al., 3,964,482 issued to Gerstel et al., U.S. Pat. No. Re 25,637 issued to Kravitz et al. and PCT application WO 96/37155. These devices typically utilize tubular or cylindrical structures generally, although Gerstel does disclose the use of other shapes, to pierce the outer layer of the skin. The piercing elements disclosed in these references generally extend perpendicular from a thin flat member, such as a pad or metal sheet.
More recently, attempts have been made to anchor the tiny piercing elements of such devices in the skin in order to keep the drug transmitting pathways open, which pathways are cut through the stratum corneum by the microprotrusions. See for example, Cormier, et al., WO 97/48440. Unfortunately, because of the extremely small size of the microprotrusions, the formation of barbs and similar anchoring elements on the microprotrusions is problematic.
The microprotrusion arrays disclosed in WO 97/48440 are in the form of a thin metal sheet having a plurality of agent-transmitting openings therethrough. The sheet has a skin proximal surface and a skin distal surface. A plurality of etched and punched mircroprotrusions extend roughly perpendicularly from the skin distal surface of the sheet. A reservoir adapted to contain (in the case of agent delivery) or receive (in the case of agent sampling) the agent is positioned on the skin distal surface of the sheet. The microprotrusion array and the agent reservoir are then pressed onto the skin surface and maintained on the skin using an adhesive overlay or similar securing means as shown in FIG. 1. Thus, the sheet member 6 having the microprotrusions 4 extending from a skin distal surface thereof is placed on the skin with the microprotrusions 4 penetrating into the skin surface. The agent reservoir 27 is shown on the skin distal side of sheet 6. The structure is held in place on the skin 30 by an overlay 3 having adhesive coated on at least the peripheral surfaces 9 thereof.
The agent reservoir 27 in the FIG. 1 device tended to be composed of soft compliant materials such as gels. Such soft compliant, and even flowable, materials were preferred with sheet member 6 since the gel material could easily flow into the openings of sheet member 6 in order to come into direct contact with skin 30.